Effect of P2Y12 Inhibitors on Organ Support–Free Survival in Critically Ill Patients Hospitalized for COVID-19
Authors: Jeffrey S. Berger, Matthew D. Neal, Lucy Z. Kornblith, Michelle N. Gong, Harmony R. Reynolds, Mary Cushman, Andrew D. Althouse, Patrick R. Lawler, Bryan J. McVerry, Keri S. Kim, Lisa Baumann Kreuziger, Scott D. Solomon, Mikhail N. Kosiborod, Scott M. Berry, Grant V. Bochicchio, Marco Contoli, Michael E. Farkouh, Joshua D. Froess, Sheetal Gandotra, Yonatan Greenstein, Erinn M. Hade, Nicholas Hanna, Kristin Hudock, Robert C. Hyzy, Fátima Ibáñez Estéllez, Nicole Iovine, Ashish K. Khanna, Pooja Khatri, Bridget-Anne Kirwan, Matthew E. Kutcher, Eric Leifer, George Lim, Renato D. Lopes, Jose L. Lopez-Sendon, James F. Luther, Lilia Nigro Maia, John G. Quigley, Lana Wahid, Jennifer G. Wilson, Ryan Zarychanski, Andrei Kindzelski, Mark W. Geraci, Judith S. Hochman, Judith S. Hochman, Matthew D. Neal, Jeffrey S. Berger, Mikhail Kosiborod, Scott Solomon, Mark Geraci, Mary Cushman, Scott Berry, Michael Farkouh, Michelle Gong, Kristin Hudock, Keri S. Kim, Lucy Z. Kornblith, Patrick R. Lawler, Aldo Maggioni, Renato Lopes, Jose Lopez-Sendon, Bridget-Anne Kirwan, Hooman Kamel, Ewan Goligher, Ryan Zarychanski, Pooja Khatri, Eric Leifer, Bryan J. McVerry, Harmony R. Reynolds, Jennifer G. Wilson, Erinn Hade, Cheng Yu, Charles Lowenstein, Orly Vardeny, Otavio Berwanger, Andrew Althouse, Ali Javaheri, Hooman Kamel Kamel, Aurea Gagliardotto, Justine Eisenberg, Cheri Barnette, Ankeet Bhatt, Brenden Everett, Aira Contreras, Stephanie Mavromichalis, Eduardo Iturrate, Margaret Gilsenan, Anna Naumova, Arlene Roberts, Jonathan Newman, Julia Levine, Michelle Chang, Alair Holden, Stephen Wisniewski, Christine Leeper, Derek Angus, Mary Martinez, Jake Schreiber, Valena Lundy-Wiggins, Joshua Froess, Ashita Sai Vadlamudi, Frank Sciurba, Alison Morris, Edvin Music, Sophie de Brouwer, Emilie Perrin, Caroline Gombault, Sandra Bula, Michael Nelson, Céline Daelemans, Laurine Paraz, Michelle Detry, Anna McGlothlin, Melanie Quintana, Amy Crawford, Elizabeth Lorenzi, Lindsay Berry, Jocelyn Chen, Anna Heath, Danielle Sin, Elhaji Diene, Ewelina Gwiszcz, Isabelle Hogan, Nancy Ringwood, Laura Fitzgerald, Haley Morin, Lucy Kornblith, Brenda Nunez-Garcia, Aaron Kornblith, Carolyn Hendrickson, Deanna Lee, Viet Nguyen, India Shelley, India Loar, Lisa Baumann Kreuziger, Stephanie Jones, John G. Quigley, Neha Atal, Bryan McVerry, David Huang, Renee Wunderly, Meredith Buxton, Tracey Roberts, Kelsey Linstrum, Amanda McNamara, Alexandra Weissman, Dylan Barbee, Emily Berryman, Jamey Frasure, Amy Sulken, Kalli Beasley, Narlina Lalani, Ashlea Mayberry, Windsor Sheryl, Roche Sindy, Jéssica Natuline Ianof, Lilian Mazza, Julia Morata, Carolina Martins Cafarella, Mayra Akimi Suiama, Daniele de Lima Franco, Jorge Escobedo, Andrea Martinez, Pedro Ohara, Douglas Assis, Chiara Manzalini, Stefania Corsi, Gianluca Campo, Paula Prieto, Rocio Prieto, Rebecca Wakeman, Christopher J. Duncan, Srikar Savaram, Alexandra Marie Taylor, Valerie J. Renard, Grace R. Dreyer, Tatyana Der, Emily R. Ko, Neil Stafford, Andrea Archibald, Oluwayemisi Mohammed, Nkiruka Azuogalanya, Thomas L. Ortel, Ari Moskowitz, Amira Mohammed , R. Duncan Hite, Harshada More, Hammad Tanzeem, Neil Ernst, Dalton Kuebel, Julia Vargas, Hena Sihota, Micah R. Whitson, Donna S. Harris, Jeffrey R Jacobson, María I. Murillo Blasco, Francisco Galiano Cuevas, Michael Plump, Bruce Cusson, Amelia Eaton, Lynnette Harris, Mhorys Pickmans, Jessica Reeves, Brandon Reeves, Kinchit Shah, Tanmay Sura, Hinna Wadhwani, Ryan Maves, Leonard Stallings, Lilia Nigro Maia, Nadielly Prado, Osvaldo Silva Junior, Cláudio Jorge, Osana Costa, Mariana Buka Buka, Danielli Frassatto, Paulo Dutra, Larissa da Silva, Nicolly Alessio, Thaise Pontana, Natalia Cordeiro, Thiago Souza, Jaqueline Mastro, Jaqueline  Souza, Cassia Pradela, Larissa Moreira, Guizela Pavon Pavon, Andreza Rodrigues, Anna Centurione, Joelma   Silva, Katia Andreoti, Renan Vectorazzo, Tamires Silva   Silva, Juliana Garcia, Ana Paula Demore, Alberto Papi, Luca Ronzoni, Jose Luis Lopez-Sendon Moreno, Itziar Pozuelo Echegaray, Chowdhury Ahsan, Aaron E. Kornblith, Carolyn M. Hendrickson, Fernando Worner, P Pastor, JL Morales, Jesus Peteiro, Rita Galeiras Vázquez, José María Sanchez-Andrade Bolaños, Muhib A Khan, Malik MHS Khan, Heather C Brooks, Matt Prekker, Zahra A. Ajani, Jorge Moisés, Jeisson Osorio, Jesús Aibar, Vidya Krishnan, Matthew C Exline, Elizabeth L Schwartz, Matthew Kutcher, Emily Grenn, Taylor Shaw, Simon Barinas, Stephanie C. Guo, Todd B. Seto, Lewis Satterwhite, Julius Gene Latorre, Lena F. Deb, Conrad W Liang, Vanessa F Audea, Nitin K Puri, Adam Green, Abhijit Duggal, Girish B. Nair, Sanjay Dogra, Jordan B Schooler, Steven C Moore, Scott Kaatz, Manila Gaddh, Bassel Atassi, Rajat Kapoor, Alvaro Alonso A, Alexander P. Hamel, Mauricio Leitao, Angela J. Rogers, Sergio Babudieri, Johanna I Busch, Hemali Patel, John Kostis, Binita Shah, Michael Matthay, Rachel M. Gropper, Anika Agrawal, Kimia Ashktorab, Bellal Joseph, Janine R E. Vintch, David Yuchno, Cristiano Perdeneiras Jaeger, Antonella dArminio Monforte, Luis R Garcia-Cortes, Blanca E Herrera-Morales, Eleonora Gashi, Seth Sokol, Paul Simonelli, Robert Sherwin, Adam Ackerman, Christos Colovos, Alexandre de Matos Soeiro, Murillo de Oliveira Antunes, Costa Tibério Augusto Oliveira, Melvin R. Echols, John P. Sheehan, Kraig T. Kumfer, Paulo Caramori, Otávio Fachinetto Casagrande, Carlos Carpio, Ester Zamarrón, Rodolfo Álvarez-Sala, Nicola Coppola, Antonio Russo, Jeffrey Berger, Mark A. Tidswell, Jay S. Steingrub, Shane O'Mahony, David T. Huang, Idelzuita Leandro Liporace, Stephen Pan, Ravi J. Shah, Akram Khan, Minn Oh, Matthew Lammi, Shane E Sanne, Todd Costantini, Allison E. Berndtson, Eduardo Mateos, Srikanth Vallurupalli, Srilakshmi Ravula, Michael Bromberg, Mark B Effron, Allyson M. Pishko, Alice Cohen, Cynthia Horta, James Jaffe
Journal: JAMA Network Open (2023)

Importance Platelet activation is a potential therapeutic target in patients with COVID-19. Objective To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care–level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support–free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR &amp;amp;gt; 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration ClinicalTrials.gov Identifier: NCT04505774